Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug‐related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug‐related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.     

Barriers to integrating personalized medicine into clinical practice: a best-worst scaling choice experiment

PurposeAs advances in genomics make genome sequencing more affordable, the availability of new genome-based diagnostic and therapeutic strategies (i.e., personalized medicine) will increase. This wave will hit front-line physicians who may be faced with a plethora of patients’ expectations of integrating genomic data into clinical care. The objective of this study was to elicit the preferences of physicians about regarding applying personalized medicine in their clinical practice as these strategies become available.MethodsUsing a best–worst scaling (BWS) choice experiment, we estimated the relative importance of attributes that influence physicians’ decision for using personalized medicine. Six attributes were included in the BWS: type of genetic tests, training for genetic testing, clinical guidelines, professional fee, privacy protection laws, and cost of genetic tests. A total of 197 physicians in British Columbia completed the experiment. Using latent class analysis (LCA), we explored the physicians’ heterogeneities in preferences.Results“Type of genetic tests” had the largest importance, suggesting that the physicians’ decision was highly influenced by the availability of genetic tests for patients’ predisposition to diseases and/or drug response. “Training” and “guidelines” were the attributes with the next highest importance. LCA identified two classes of physicians. Relative to class 2, class 1 had a larger weight for the “type of genetic tests,” but smaller weights for “professional fee” and “cost of tests.”ConclusionWe measured relative importance of factors that affect the decision of physicians to incorporate personalized medicine in their practice. These results can be used to design the policies for supporting physicians and facilitating the use of personalized medicine in the future.Genet Med 2012:14(5):520–526     

Relation mining experiments in the pharmacogenomics domain

The mutual interactions among genes, diseases, and drugs are at the heart of biomedical research, and are especially important for the pharmacological industry. The recent trend towards personalized medicine makes it increasingly relevant to be able to tailor drugs to specific genetic makeups. The pharmacogenetics and pharmacogenomics knowledge base (PharmGKB) aims at capturing relevant information about such interactions from several sources, including curation of the biomedical literature. Advanced text mining tools which can support the process of manual curation are increasingly necessary in order to cope with the deluge of new published results. However, effective evaluation of those tools requires the availability of manually curated data as gold standard. In this paper we discuss how the existing PharmGKB database can be used for such an evaluation task in a way similar to the usage of gold standard data derived from protein-protein interaction databases in one of the recent BioCreative shared tasks. Additionally, we present our own considerations and results on the feasibility and difficulty of such a task.     

Prevention and treatment of infectious diseases by traditional Chinese medicine: a commentary

The present review aimed to summarize the effectiveness and features of traditional Chinese medicine (TCM) for the treatment of infectious diseases and to discuss the limitation of the development of TCM. The personalized medicine with TCM exerts a curative effect on viral and bacterial infectious diseases with unique advantages on the improvement of clinical manifestation, pathogen inhibition, and organ recovery during severe and drug‐resistant infection. The deficiency of personalized medicine with TCM lies in that the current research design of TCM primarily focuses on the study of the effective components and material basis of Chinese herbs at the cellular, molecular, and genetic level, while ignoring the guidance of the TCM syndrome differentiation theory, which is the core concept of individualized treatment. Personalized medicine with TCM has a broad prospective for infectious diseases due to the specific efficacy and advantages. While the curative effect of individualized treatment with TCM cannot be excluded from the TCM syndrome differentiation theory, the study of personalized medicine with TCM for infectious diseases urgently requires a unified standardization of the clinical syndrome differentiation and the evolution rule of infectious diseases by TCM theory.     

The curious 2000-year case of asthma

Millions worldwide have asthma, with the numbers succumbing increasing sharply in the past two decades. After 2000 years of scientific study, who succumbs to asthma when is as puzzling as who regains health when and how. The discipline of psychosomatic medicine and science investigates and treats diseases like asthma that typically confound general medicine. Still psychosomatic medicine, like general medicine, only manages but does not remedy asthma, which can currently only be in remission but not cured. This historical review reveals the progress and missteps that have been made in the study and treatment of asthma by comparing the general medicine approach with the major research findings on asthma published over 60 years in Psychosomatic Medicine. Research has identified antecedent, collateral, and subsequent factors to scientifically describe and control this disease in terms of diagnosis, management, and treatment. Paradoxically and regrettably, the prognosis for those with asthma is worse than ever. Curious also that a noninfectious disease should spread so rapidly and mostly for specific groups identified by variables like age, gender, ethnicity, and socioeconomic status. Furthermore, partial, not full, family concordance indicates merely genetic influence, not determination. General medicine now focuses on enumerating the range of environmental and situational triggers, or stimuli, producing asthma and describing the pathophysiology of bronchial inflammation. With a more comprehensive multifactorial approach, psychosomatic medicine seems well suited to investigate further the physiological, psychological, social, and environmental factors implicated in this medical conundrum. A future challenge for psychosomatic medicine is to stem the tide of rising prevalence and cure the disease of asthma.     

Pharmacogenetics and pharmacogenomics in rheumatology

Pharmacogenetics and pharmacogenomics deal with possible associations of a single genetic polymorphism or those of multiple gene profiles with responses to drugs. In rheumatology, genes and gene signatures may be associated with altered efficacy and/or safety of anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs) and biologics. In brief, genes of cytochrome P450, other enzymes involved in drug metabolism, transporters and some cytokines have been associated with responses to and toxicity of non-steroidal anti-inflammatory drugs, corticosteroids and DMARDs. The efficacy of biologics may be related to alterations in cytokine, chemokine and FcγR genes. Numerous studies reported multiple genetic signatures in association with responses to biologics; however, data are inconclusive. More, focused studies carried out in larger patient cohorts, using pre-selected genes, may be needed in order to determine the future of pharmacogenetics and pharmacogenomics as tools for personalized medicine in rheumatology.     

Barriers for integrating personalized medicine into clinical practice: A qualitative analysis

Personalized medicine—tailoring interventions based on individual's genetic information—will likely change routine clinical practice in the future. Yet, how practitioners plan to apply genetic information to inform medical decision making remains unclear. We aimed to investigate physician's perception about the future role of personalized medicine, and to identify the factors that influence their decision in using genetic testing in their practice. We conducted three semi‐structured focus groups in three health regions (Fraser, Vancouver coastal, and Interior) in British Columbia, Canada. In the focus groups, participants discussed four topics on personalized medicine: (i) physicians' general understanding, (ii) advantages and disadvantages, (iii) potential impact and role in future clinical practice, and (iv) perceived barriers to integrating personalized medicine into clinical practice. Approximately 36% (n = 9) of physicians self‐reported that they were not familiar with the concept of personalized medicine. After introducing the concept, the majority of physicians (68%, n = 19 of 28) were interested in incorporating personalized medicine in their practice, provided they have access to the necessary knowledge and tools. Participants mostly believed that genetic developments will directly affect their practice in the future. The key concerns highlighted were physician's access to clinical guidelines and training opportunities for the use of genetic testing and data interpretation. Despite the challenges that personalized medicine can create, in general, physicians in the focus groups expressed strong interest in using genetic information in their practice if they have access to the necessary knowledge and tools. © 2013 Wiley Periodicals, Inc.     

过敏性哮喘的研究进展

过敏性哮喘患病率在世界多地区呈现快速上升。其发病机制与复杂的遗传背景和环境因素相关。屏障系统如气道上皮细胞接受刺激,分泌介质,传递信号活化局部组织微环境中天然免疫系统细胞,如天然淋巴样细胞(ILC),及许多效应分子被上调或下调。这些免疫微环境的改变与获得性免疫系统交互作用而启动疾病过程。其中2 型ILC 能与神经递质相互作用提示神经系统与区域免疫系统交互作用调节局部组织功能。有证据显示表观基因组变化、黏膜微生态改变等, 均参与疾病始动、发展及转归。对疾病表型的更深入认识,能有助于从根据病人疾病表型选择治疗,而转向根据疾病机制选择适合治疗方案的病人。此外,对治疗方案的选择和评估,均需要有更多更可靠的生物标志物。实验研究也需要更能真实映象人体的实验模型。本文综述这些方面近年来的研究进展。     

Nutrigenetics and nutraceuticals: the next wave riding on personalized medicine

The Human Genome Project and subsequent identification of single nucleotide polymorphisms (SNPs) within populations has played a major role in predicting individual response to drugs (pharmacogenetics) leading to the concept of "personalized medicine." Nutritional genomics is a recent off-shoot of this genetic revolution that includes (1) nutrigenomics: the study of interaction of dietary components with the genome and the resulting proteonomic and metabolomic changes; and (2) nutrigenetics: understanding the gene-based differences in response to dietary components and developing nutraceuticals that are most compatible with health based on individual genetic makeup. Despite the extensive data on genetic polymorphisms in humans, its translation into medical practice has been slow because of the time required to accumulate population data on SNP incidence, understand the significance of a given SNP in disease, and develop suitable diagnostic tests. Nutrigenomics revitalized the field by showing that nutrients and botanicals can interact with the genome and modify subsequent gene expression, which has provided a great impetus for nutrigenetic research and nutraceutical development based on nutrigenetics. Polymorphisms in methlyene tetrahydrofolate reductase (MTHFR) (involved in folate metabolism), apolipoprotein E (Apo E) and ApoA1 (in cardiovascular disease), and leptin/leptin receptor (obesity) genes are some good examples for understanding basic nutrigenetics. Developing nutraceuticals to prevent and manage thrombosis risk in women with thrombophilic gene mutations are discussed in the context of the opportunities that exist at the nutrigenetic/pharmacogenetic interphase leading to "personalized nutrition." Further research on individual differences in genetic profiles and nutrient requirements will help establish nutrigenetics as an essential discipline for nutrition and dietetics practice.     

How the practice of allergy shows the promise and challenge of personalized medicine

Personalized medicine seeks to stratify therapies according to individual characteristics, and by so doing improve effectiveness and reduce complications. However, there are not many models of care that is highly stratified within a single diagnosis in this manner. One potential model is the practice of allergy, in which care is tailored to specific allergens for individual patients within the broader context of care for rhinitis or asthma. Allergists have already confronted many of the same regulatory issues anticipated for personalized medicine. The history of allergy practice also anticipates some of the patient safety concerns that may arise from tracking and using highly personalized medical information. Finally, the therapy of allergy and asthma has been at the forefront of attempts to incorporate pharmacogenomics information into patient care. Individualized therapy has always been central to the practice of allergy, and so provides a useful proving ground for personalized medicine as a concept of care.     

Effect of cytokine and pharmacogenomic genetic polymorphisms in transplantation

Consolidating the information that we have on pharmacogenetics and on cytokine genetics to produce patient-oriented individualized drug regimens is an important challenge in transplantation medicine. Using a multi-variant approach based on genetic profile and other relevant clinical factors a score system may be developed to predict the severity of rejection, infection, or other complications associated with transplantation. The ultimate goal of these studies is to improve patient outcome through individualized drug regimens.     

Asthma treatment in the 21st century

Asthma treatment is evolving as we enter the 21st century. This review focuses on several different areas of asthma treatment now in evolution. These include: (1) the proper role of various asthma controllers--either already approved or under investigation--besides inhaled corticosteriods in asthma therapy; (2) the potential role for immune and cytokine modulation for asthma therapy; (3) the potential role for pharmacogenetics in asthma therapy; and (4) whether single-inhaler therapy with a combination of an inhaled corticosteriod and a long-acted beta-agonist could be used for both maintenance and rescue in patients with asthma.     

Age‐related macular degeneration—clinical review and genetics update

Age‐related macular degeneration (AMD) is the leading cause of central vision impairment in persons over the age of 50 years in developed countries. Both genetic and non‐genetic (environmental) factors play major roles in AMD etiology, and multiple gene variants and lifestyle factors such as smoking have been associated with the disease. While dissecting the basic etiology of the disease remains a major challenge, current genetic knowledge has provided opportunities for improved risk assessment, molecular diagnosis and clinical testing of genetic variants in AMD treatment and management. This review addresses the potential of translating the wealth of genetic findings for improved risk prediction and therapeutic intervention in AMD patients. Finally, we discuss the recent advancement in genetics and genomics and the future prospective of personalized medicine in AMD patients.     

New approaches to personalized medicine for asthma: where are we?

Access to an electronic medical record is essential for personalized medicine. Currently, only 40% of US physicians have such access, but this is rapidly changing. It is expected that 100,000 Americans will have their whole genome sequenced in 2012. The cost of such sequencing is rapidly dropping, and is estimated to be $1000 by 2013. These technological advances will make interpretation of whole genome sequence data a major clinical challenge for the foreseeable future. At present, a relatively small number of genes have been identified to determine drug treatment response phenotypes for asthma. It is anticipated that this will dramatically increase over the next 10 years as personalized medicine becomes more of a reality for asthma patients.     

Advances and recent developments in asthma in 2020

In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19.     

Genetic risk factors for the development of allergic disease identified by genome‐wide association

An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome‐Wide Association Studies (GWAS), a hypothesis‐free method of interrogating large numbers of common variants spanning the entire genome in disease and non‐disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities.     

Inferring the effect of genomic variation in the new era of genomics

Accurate and detailed understanding of the effects of variants in the coding and noncoding regions of the genome is the next big challenge in the new genomic era of personalized medicine, especially to tackle newer findings of genetic and phenotypic heterogeneity of diseases. This is necessary to resolve the gene‐variant–disease relationship, the pathogenic variant spectrum of genes, pathogenic variants with variable clinical consequences, and multiloci diseases. In turn, this will facilitate patient recruitment for relevant clinical trials. In this review, we describe the trends in research at the intersection of basic and clinical genomics aiming to (a) overcome molecular diagnostic challenges and increase the clinical utility of next‐generation sequencing (NGS) platforms, (b) elucidate variants associated with disease, (c) determine overall genomic complexity including epistasis, complex inheritance patterns such as “synergistic heterozygosity,” digenic/multigenic inheritance, modifier effect, and rare variant load. We describe the newly emerging field of integrated functional genomics, in vivo or in vitro large‐scale functional approaches, statistical bioinformatics algorithms that support NGS genomics data to interpret variants for timely clinical diagnostics and disease management. Thus, facilitating the discovery of new therapeutic or biomarker options, and their roles in the future of personalized medicine.     

Narrowing the gap of personalized medicine in emerging countries: the case of multiple endocrine neoplasias in Brazil

The finished version of the human genome sequence was completed in 2003, and this event initiated a revolution in medical practice, which is usually referred to as the age of genomic or personalized medicine. Genomic medicine aims to be predictive, personalized, preventive, and also participative (4Ps). It offers a new approach to several pathological conditions, although its impact so far has been more evident in mendelian diseases. This article briefly reviews the potential advantages of this approach, and also some issues that may arise in the attempt to apply the accumulated knowledge from genomic medicine to clinical practice in emerging countries. The advantages of applying genomic medicine into clinical practice are obvious, enabling prediction, prevention, and early diagnosis and treatment of several genetic disorders. However, there are also some issues, such as those related to: (a) the need for approval of a law equivalent to the Genetic Information Nondiscrimination Act, which was approved in 2008 in the USA; (b) the need for private and public funding for genetics and genomics; (c) the need for development of innovative healthcare systems that may substantially cut costs (e.g. costs of periodic medical followup); (d) the need for new graduate and postgraduate curricula in which genomic medicine is emphasized; and (e) the need to adequately inform the population and possible consumers of genetic testing, with reference to the basic aspects of genomic medicine.     

Pharmacogenetics and pharmacogenomics: recent developments,their clinical relevance and some ethical,social, and legal implications

In recent debates on novel procedures of molecular medicine pharmacogenomics is attracting more and more attention as a genotype-based approach for improving safety and efficacy of the use of therapeutic substances. Promoted by basic knowledge generated in the field of medical genomics, facilitated by novel technological tools for mapping genetic variation in individuals, and supported by results of initial clinical studies linking specific genotypes to metabolic characteristics of individuals important for assessing drug response, procedures of pharmacogenetics and pharmacogenomics now are starting to impact significantly on clinical research and development and medical practice. In this situation assessing the goals, risk, and benefits of pharmacogenetics and pharmacogenomics is essential for the medically successful, ethically justifiable, and socially acceptable implementation of genotype-based diagnosis and pharmacotherapy. We discuss the current state of the art in pharmacogenetics and pharmacogenomics and introduce a model for evidence based assessment of its goals, risk, and benefits. We differentiate here between pragmatic and normative issues in the development of pharmacogenomics in order to contrast prevailing, insufficiently interest-based modes of public technology assessment with the evidence-based mode that can be established as part of clinical study design. Finally, we provide a framework for the analysis of social accountability that can be used for technology development and technology assessment with regard to pharmacogenomics in particular and molecular medicine in general.